Title: Extremely long tumor retention, on-demand releasing Nano-Taxel for eradicating ovarian cancers Project Summary Treatment of late-stage ovarian cancer remains one of the greatest challenges for gynecologic oncologists. The clinical efficacy of paclitaxel (PTX), a first-line chemotherapy, is limited due to its severe adverse effect and poor drug exposure and delivery to target tissues. Abraxane (Albumin-bound paclitaxel, particle size ~130 nm) was designed to overcome the dose-limiting toxicity of standard PTX. However, Abraxane does not function as a true nanoparticle, because the control over drug properties, such as release rates, is not possible with this formulation. The safety and effectiveness of Abraxane in ovarian cancer patients have not been established. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. It has also been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart PTX loaded micellar nanoparticles (Nano-Taxel) with smaller size (~20 nm), extremely long tumor retention (at least 12 days), and on-demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against ovarian cancer, therefore have great commercial potentials to lead to a marketable PTX-nanoformulation for the treatment of ovarian cancer. The overall goal of this proposal is to develop highly effective and less toxic micellar formulation of PTX (Nano-Taxel) against ovarian cancer in preclinical animal models in Phase I studies, and perform current good manufacturing practice (cGMP) production & IND-enabling pharmacology and toxicology studies in Phase II studies that will eventually lead to an IND filing to the FDA for a first-in- human phase I clinical trial. Our hypotheses are: (i) The smaller and extremely long tumor retention micelle formulation of PTX, compared to its free form are more efficacious and less toxic against ovarian cancer; (ii) The on-demand drug releasing properties of Nano-Taxel achieved by boronate crosslinking strategy will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells, therefore will greatly improve the efficacy and toxicity profile; and (iii) OA02, a highly potent targeting ligand, when decorated on the surface of Nano-Taxel to facilitate the in vivo delivery to ovarian cancer, will further improve its therapeutic index. State-of-the-art design of nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of ease of large- scale production, fine-tunable and highly reproducible structure and properties. It will address many translational barriers of nanotherapeutic agents. The use of boronate crosslinked micelles with extremely long tumor retention and on-demand drug releasing properties to delivery PTX to ovarian cancer is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumors. It is expected that this research will lead to new approach for ovarian cancer therapy.